Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis-Based Computer-Aided Molecular Design
MAYO CLINIC ROCHESTER MN
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Botulinum neurotoxin serotype A BoNTA causes a life-threatening neuroparalytic disease known as botulism. Current treatment for postexposure of BoNTA uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Effective small-molecule inhibitors of BoNTA endopeptidase BoNTAc are desirable because such inhibitors potentially can neutralize the intracellular BoNTA and offer complementary treatment for botulism. Previously, we reported a serotype-selective, small-molecule BoNTAc inhibitor with a K1pp value of 3.8 0.8 M. This inhibitor was developed by lead identification using virtual screening followed by computer-aided optimization of a lead with an IC50 value of 100 m.
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